Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase.
Topical application of phorbol myristate acetate (PMA) elicits intense local inflammation that facilitates outgrowth of premalignant lesions in skin after carcinogen exposure. The inflammatory response to PMA treatment activates immune stimulatory mechanisms. However, we show here that PMA exposure also induces plasmacytoid dendritic cells (pDCs) in local draining lymph nodes (dLNs) to express indoleamine 2,3 dioxygenase (IDO), which confers T cell suppressor activity on pDCs. The induced IDO-mediated inhibitory activity in this subset of pDCs was potent, dominantly suppressing the T cell stimulatory activity of other DCs that comprise the major fraction of dLN DCs. IDO induction in pDCs depended on inflammatory signaling by means of IFN type I and II receptors, the TLR/IL-1 signaling adaptor MyD88, and on cellular stress responses to amino acid withdrawal by means of the integrated stress response kinase GCN2. Consistent with the hypothesis that T cell suppressive, IDO(+) pDCs elicited by PMA exposure create local immune privilege that favors tumor development, IDO-deficient mice exhibited a robust tumor-resistant phenotype in the standard DMBA/PMA 2-stage carcinogenesis model of skin papilloma formation. Thus, IDO is a key immunosuppressive factor that facilitates tumor progression in this setting of chronic inflammation driven by repeated topical PMA exposure.
Muller
Alexander J
AJ
Immunotherapy and Cancer Centers, Flow Cytometry Core Facility, and Departments of Pediatrics and Medicine, Medical College of Georgia, Augusta, GA 30912, USA.
Sharma
Madhav D
MD
Chandler
Phillip R
PR
Duhadaway
James B
JB
Everhart
Mary E
ME
Johnson
Burles A
BA
Kahler
David J
DJ
Pihkala
Jeanene
J
Soler
Alejandro Peralta
AP
Munn
David H
DH
Prendergast
George C
GC
Mellor
Andrew L
AL
D000818:Animals; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D003877:Dermatitis, Contact / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D007108:Immune Tolerance / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010212:Papilloma / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D013755:Tetradecanoylphorbol Acetate